Effects of Combined Oral Conjugated Estrogens and Medroxyprogesterone Acetate on Brain Infarction Size after Experimental Stroke in Rat

Abstract

The reason that estrogen is strongly protective in various estrogen-deficient animal models while seemingly detrimental in postmenopausal women remains unclear. It hypothesized that prolonged oral medroxyprogesterone (MPA) plus oral conjugated equine estrogens (CEE) diminishes estrogen ability to reduce stroke damage in the rodent stroke model. To test the hypothesis, we fed ovariectomized rats CEE or MPA, or a combination of CEE and MPA (CEP), before inducing 120 min of reversible focal stroke, using the intraluminal filament model. After 22 h reperfusion, the brains were harvested and infarction volumes were quantified. Treatment with CEE alone or with CEP reduced cortical infarction volume. However, CEP failed to provide ischemic protection in subcortical regions. It was concluded that CEE alone, or with CEP, is neuroprotective in the cortex, but interactive effects between the hormones may counteract CEE beneficial effects in subcortical brain regions.

Reduced metabolites mediate neuroprotective effects of progesterone in the adult rat hippocampus. The synthetic progestin medroxyprogesterone acetate (Provera) is not neuroprotective

“…In addition, both estradiol and progesterone exert a potentiation of glutamate-mediated rises in intracellular calcium in neurons, while MPA blocks the effect of estradiol (Nilsen and Brinton, 2002b). Furthermore, MPA has been shown to decrease the neuroprotective effect of oral conjugated estrogens in subcortical brain regions after experimental stroke in rat (Littleton-Kearney et al, 2005).…”

“…Furthermore, progesterone has neuroprotective properties in different experimental models of neurodegeneration, including excitotoxicity, traumatic brain injury, stroke, spinal cord trauma, spinal cord motoneuron disease, and motoneuron axotomy (Yu, 1989;Ogata et al, 1993;Roof et al, 1994Roof et al, , 1996Roof et al, , 1997Asbury et al, 1998;Chen et al, 1999;Thomas et al, 1999;Vongher and Frye, 1999;Kumon et al, 2000;Callier et al, 2001;Cervantes et al, 2002;Gonzalez Deniselle et al, 2002;Labombarda et al, 2002;Murphy et al, 2002;Nilsen and Brinton, 2002a;Shear et al, 2002;Hoffman et al, 2003;Djebaili et al, 2004;Gibson and Murphy, 2004;Grossman et al, 2004;Morali et al, 2005;Stein, 2005;Robertson et al, 2006). In contrast, the synthetic progestin medroxyprogesterone acetate (MPA, Provera) is not neuroprotective against glutamate toxicity in vitro and reduces the protective effects of estradiol in vitro and in vivo (Nilsen and Brinton, 2002a,b;Littleton-Kearney et al, 2005). It is highly relevant to understand the differences among the effects and mechanisms of action of natural progestins and MPA in the brain, because MPA is a commonly used progestin for postmenopausal hormone replacement therapy and is a widely used female contraceptive (Hapgood et al, 2004).…”

Conjugated equine estrogen enhances rats' cognitive, anxiety, and social behavior

“…CEE promotes neuronal growth in brain regions important for the functional effects that we observed, such as the cortex, hippocampus, and basal forebrain [19]. CEE, or specific components of it, have neuroprotective effects on β-amyloid or glutamate toxicity models and in experimental ischemia [20][21][22]. Thus, CEE can have beneficial effects; however, the underlying mechanisms need to be elucidated.…”

Estrogens and progesterone as neuroprotectants: what animal models teach us

“…Basic science studies have, in fact, demonstrated that progesterone is neuroprotective (19,26,28,29,(38)(39)(40), while the synthetic progestin, MPA, is not (38,39,41). For example, in a model of stroke (reversible focal stroke using the intraluminal filament model followed by 22 hours of reperfusion), MPA diminished the protective effects of conjugated equine estrogens (CEE) and MPA diminished estrogen's ability to reduce stroke damage (41).…”